Process for preparing snuff composition

ABSTRACT

A method for the preparation of a nicotine-cellulose combination, the method comprising simultaneous loading of the nicotine on the cellulose and agglomeration of the particles so as to obtain a suitably loaded combination with a mean particle size that is suitable for use e.g. in snuff compositions packed in pouches of gauze or other materials with opening. The invention further relates to the use of such a nicotine-cellulose combination for the preparation of a snuff composition for achievement of a fast onset of action of nicotine after application of the snuff composition to the oral cavity of a subject, wherein the composition has a high release rate so that when subjected to an in vitro dissolution test about 45% or more of the total content of nicotine is released within 30 minutes. Moreover, the invention relates to an improved snuff composition for application to the oral cavity.

FIELD OF THE INVENTION

The present invention relates to a method for the preparation of anicotine-cellulose combination suitable for use in a snuff composition,notably for achievement of a fast onset of action of nicotine afterapplication of the snuff composition to the oral cavity of a subject.The method of the present invention provides a nicotine-cellulosecombination with a mean particle size that is suitable for use in thosecases where the snuff composition is packaged in e.g. gauze or otherkinds of material that have openings of a certain size. At present nocellulose quality for phamaceutical use is commercially available thathas a suitably relatively large particle size (i.e. about 200 μm ormore). In a specific embodiment, the composition has a high release rateso that when subjected to an in vitro dissolution test about 45% or moreof the total content of nicotine is released within 30 minutes.Moreover, the invention relates to an improved snuff composition forapplication to the oral cavity.

BACKGROUND OF THE INVENTION

Wet snuff is a variant of nicotine addition mainly seen in the US andScandinavia and particularly in Sweden, where this variant is used on adaily basis by approximately 20% of men.

Although wet snuff is not implicated in the cardiovascular and lungdisease morbidity and mortality caused by smoking, the content ofnitrosamines poses a potential hazard for some cancer diseases. It istherefore of interest to make available to consumers a snuff-likeproduct while minimising this potential hazard.

The vascular area at the administration route and the fact that thesnuff is fixed over a long period of time gives an opportunity for botha quick and thorough uptake of nicotine over the mucosa. To develop anew medicated snuff bag—Snuff Similar—with similar nicotine effects butwithout the carcinogenic risks derived from the tobacco was theobjective for this project. To reach other countries in Europe andworldwide, one approach would be to have a product that is more cleanand more socially acceptable in its appearance. By using the whitecellulose complex this could be achieved. A more socially acceptablealternative might also potentially increase usage, especially amongwomen.

Due to the slow wetting and thereby release, migration and absorption ofnicotine, nicotine release from snuff bags is incomplete in vivo. Apresent snuff variant on the market is “General white” (Swedish MatchAB), has a loaded amount of 8.0 mg nicotine per snuff bag and anapproximate in vitro release of 1.4 mg over a period of 30 minutes. Therelease in vivo is consequently less than 20%. This is mainly due to thelow amount of saliva available to dissolve the nicotine and to the factthat the snuff bag is kept in place over the time of administration.Accordingly, in order to load as little nicotine as possible, there is aneed for snuff bag compositions, which have a higher total release ofnicotine. This will also imply that less nicotine is used in the methodfor preparation of such snuff compositions, which is also beneficialfrom an economic and an environmental point of view.

The foregoing has outlined rather broadly the features and technicaladvantages of the present invention in order that the detaileddescription of the invention that follows may be better understood.Additional features and advantages of the invention will be describedhereinafter which form the subject of the claims of the invention. Itshould be appreciated by those skilled in the art that the conceptionand specific embodiment disclosed may be readily utilized as a basis formodifying or designing other structures for carrying out the samepurposes of the present invention. It should also be realized by thoseskilled in the art that such equivalent constructions do not depart fromthe spirit and scope of the invention as set forth in the appendedclaims. The novel features which are believed to be characteristic ofthe invention, both as to its organization and method of operation,together with further objects and advantages will be better understoodfrom the following description when considered in connection with theaccompanying figures. It is to be expressly understood, however, thateach of the figures is provided for the purpose of illustration anddescription only and is not intended as a definition of the limits ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a further development of previously describedfinding by the inventors (cf unpublished patent applicationPCT/EP2007/002343 which is hereby incorporated in its entirety).Moreover, the compositions specifically mentioned in this applicationare not subject of the present invention and may be disclaimed, ifneeded. The present inventors have observed that the compositionsdescribed in the above-identified PCT application in some cases have atoo small mean particle size to enable the composition to besufficiently retained in e.g. gauze pouches. Normally, gauze poucheshave a mesh of about 200 μm, and in order to ensure that the compositiondoes not fall out through the openings, the nicotine-cellulosecombination must have a mean particle size of at least about 200 μm.Moreover, the present invention also relates to the use of such anicotine-cellulose combination for the preparation of a snuffcomposition for achievement of a fast onset of action of nicotine afterapplication of the snuff composition to the oral cavity of a subject.The composition has a high release rate so that when subjected to an invitro dissolution test about 45% or more of the total content ofnicotine is released within 30 minutes.

In general the onset of the nicotine effect is within 5 minutes such as,e.g. within 4 minutes, within 3 minutes, within 2 minutes or within 1.5minutes after application of composition between the lip and the teethof a subject.

In the present context the term “nicotine-cellulose combination” isintended to denote a solid material composed of a cellulose which hassorbed (adsorbed and/or absorbed) a well-defined amount of nicotine(either as free base or as a pharmaceutically acceptable salt, complexor solvate) e.g. in voids or pores within the cellulose. The terms“nicotine-cellulose adduct” and “nicotine-cellulose carrier complex” asused herein are intended to have the same meaning as the term“nicotine-cellulose combination”. As used herein cellulose is an exampleof a carrier.

In WO 2004/056363 (to the same Applicant) is described such anicotine-cellulose combination for release of nicotine. However, thereis no disclosure of the use of such a material for the preparation of asnuff composition for use in the oral cavity. The present inventors havefound that it is necessary to load the cellulose with nicotine in thesame process as agglomeration of the cellulose/nicotine-cellulosecombination is carried out. If the two steps are carried out in twoseparate processes, the following has been observed:

i) If agglomeration is carried out in a first step (i.e. the meanparticle size of the cellulose employed has been increased to a certainsize—normally at least 200 μm such as, e.g. at least 250 μm, at least300 μm, at least 350 μm or at least about 400 μm) it is difficult toload the agglomerated cellulose with a reproducible concentration ofnicotine. This is most likely due to a competing process, whereby liquidalready filling up internal voids and/or pores must be replaced bynicotine, but once the voids or pores already are filled, it becomesmore difficult to displace the liquid and fill the voids/pores withnicotine.ii) if agglomeration is carried out after nicotine has been loaded tothe cellulose, the liquid employed in the agglomeration processinitiates a release of the nicotine from the cellulose, i.e. either nonicotine is present in the voids/pores after such a process or at leasta much lower concentration than desired is present.

Accordingly, the present inventors have developed a novel method forloading the cellulose with nicotine and at the same time building up alarger mean particle size.

Moreover, the present inventors have found that the use of such anicotine-cellulose combination is especially suitable for use in a snuffcomposition as such a snuff composition, on the one hand releasesnicotine relatively fast and thereby enables a fast onset of thenicotine effect, and on the other hand enables the nicotine content inthe snuff composition to be completely or almost completely releasedafter application in the oral cavity. The complete or almost completerelease is also seen after encapsulating of the snuff composition in asuitable bag, pouch or membrane. The bag or pouch may be of any suitablematerial e.g. wowen or non-wowen fabric (e.g. cotton, fleece etc.), heatsealable non-wowen cellulose or other polymeric materials such as asynthetic, semi-synthetic or natural polymeric material as describedherein. A material suitable for use must provide a semi-permeablemembrane layer to prevent the powder or composition from leaving the bagor pouch during use. Suitable materials are also those that do not havea significant impact on the release of nicotine from the composition. Tothe best of the inventor's knowledge, the nicotine/tobacco snuffproducts available on the market today only releases a part of thenicotine contained in the snuff product (see the Examples herein).

The snuff is normally in the form of a bag or pouch suitable for buccaladministration (e.g. to be inserted between the lip and the teeth) andthe bag or pouch comprises the nicotine in the form of anicotine-cellulose combination. In a particular interesting embodiment,the cellulose is microcrystalline cellulose having a mean particle sizeof about 180 μM. An example of a suitable quality is e.g. Avicel PH-200.

The snuff composition according to the present invention may alsocomprise one or more pharmaceutically acceptable excipients or additivesthat are suitable for buccal administration. Such agents include—but arenot limited to—fillers, binders, wetting agents, stabilizing agents,coloring agents, surface active agents, pH adjusting agents, absorptionenhancers, taste-masking agents, flavoring agents, texture-improvingagents, etc.

The nicotine-cellulose combination (normally together with one or morepharmaceutically acceptable excipients or additives) may be enclosed ina membrane material. The membrane may be a natural, synthetic,semi-synthetic hydrophilic or hydrophobic membrane. It may be made fromone or more biocompatible and physiologically acceptable polymericmaterial. Examples of suitable membrane materials are cellulose acetateand derivatives thereof, carboxymethyl cellulose, polycellulose ester,other cellulose derivatives including ethylcellulose, propylcellulose,polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylacetate, polymers of methacrylates and acrylates, natural rubber,polycarbonate, polyethylene terephthalate, polyester, polyamide andnylon. Other suitable materials are mentioned herein before.

In keeping with long-standing patent law convention, the words “a” and“an” when used in the present specification in concert with the wordcomprising, including the claims, denote “one or more.” As used herein“another” may mean at least a second or more. Some embodiments of theinvention may consist of or consist essentially of one or more elements,method steps, and/or methods of the invention. It is contemplated thatany method or composition described herein can be implemented withrespect to any other method or composition described herein.

The invention relates to a snuff composition for buccal administrationin the cheek pouch between the cheek and the jaw or under the lip. Thecomposition may include tobacco.

The use of tobacco is deeply rooted in a large part of the worldpopulation. In the Scandinavian countries and in particular Sweden theuse of moist snuff (snus) is very common as an alternative to smoking.Snuff is fermented and milled/grinded tobacco with a relatively largewater content (40-60% w/w), normally to be used under the front upperlip of a human being.

Tobacco itself varies somewhat in nicotine content due to its naturalorigin. To adjust the nicotine release in moist snuff, various buffersystems may be added, e.g. carbonates. The moist snuff is either packedloosely, as bulk in a box or as single doses in small non-woven bags. Anumber of the filled and sealed bags are then packed in a box.

The moist snuff as a single dose has become popular due to the ease ofuse compared to the bulk product. The popularity of moist snuff is mostprobably due to its pharmacological nicotine absorption profile. Thedose of nicotine and speed of absorption is approximately 10 ng per mlover 10 minutes though this may vary between brands. Measurements ofplasma nicotine concentrations after a single day of moist snuffconsumption also yielded levels similar to cigarette use. The kineticsare slightly slower compared to the kinetics when smoking tobacco, suchas e.g. cigarettes and cigars; however, the overall amount of nicotineabsorbed is higher when snuff is employed.

A snuff composition according to the invention comprises nicotine, or apharmaceutically acceptable salt, solvate, complex, adduct, orderivative thereof. When subjected to an in vitro dissolution test asdescribed herein for 30 minutes about 30% or more of the total contentof nicotine is released. This requirement with respect to in vitrorelease ensures that a sufficient amount of nicotine is rapidlyavailable for absorption through the oral mucosa. In particularembodiments, about 35% or more such as, e.g., about 40% or more, about42% or more, about 45% or more, about 50% or more of the total contentof nicotine is released. In embodiments of particular interest, therelease of nicotine is about 45% or more of the total content ofnicotine within 30 minutes (in an in vitro test). Notably, the releasewithin this period of time is about 50% or more such as, e.g., about 60%or more, about 70% or more or about 75% or more of the total content ofnicotine in the snuff composition. The same applies to snuffcompositions encapsulated in a polymeric membrane as described herein.

One important feature of the present invention is that the snuffcomposition leads to a rapid appearance of nicotine in the plasma.Accordingly, in general the in vivo uptake of nicotine 30 minutes afterbuccal administration corresponds to at least about 30% of the totalcontent of nicotine in the snuff. As seen from the examples herein thesnuff composition can be formulated so that the in vivo release ofnicotine 30 minutes after buccal administration is higher, i.e. itcorresponds to at least about 35% such as, e.g., at least about 40%, atleast about 42%, at least about 45%, at least about 50%, at least about55%, at least about 60%, at least about 65%, at least about 70% or atleast about 75% of the total content of nicotine in the snuff.

A snuff composition according to the invention normally comprises acarrier comprising internal voids. Such voids may at least partiallycomprise said nicotine. The carrier is typically insoluble in water orhas a low solubility in water. Thus, it typically has a solubility inwater at room temperature of less than 1% w/w.

A particular suitable carrier for use in a snuff composition of theinvention is a cellulose, such as a microcrystalline cellulose (“mcc”).The cellulose may be synthetic or semi-synthetic celluloses, or it maybe derived from natural celluloses. It is normally crystalline such asmicrocrystalline. Certain specific embodiments may also utilize otherforms of carriers, in addition to or including mcc, such as but notlimited to fibrous material or carbohydrates including cellulose(including hemicellulose, celluloses with different crystallinities andstructures (e.g., varying structures including solid fibers, andaddition or including fibers or the like in various structures such asweb-like structures and/or other structures), including naturallyoccurring celluloses including Cladophora sp. Algae cellulose or thelike), dextran, agarose, agar, pectin, alginate, xanthan, chitosan,starch (including potato starch, shoti starch) etc. or mixtures thereof.While not intended to be bound by theory, it is believed as of the timeof this patent application that nicotine may interact the carrier (forexample, mcc or other suitable carrier including other cellulosecarriers) by absorbing into and/or adsorbing onto the carrier. Suchinteraction is completely or nearly completely reversible.

The microcrystalline cellulose may be selected from the group consistingof AVICEL® grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113,PH-200, PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20 and EMOCEL®grades 50M and 90M, and the like, and mixtures thereof.

Suitable carriers may also be those disclosed in WO 2004/064811, whichis hereby included by reference.

More specifically, it is contemplated that a relatively high surfacearea may be of importance for a carrier that is suitable for use.Accordingly, the specific surface area of suitable carriers is normallyat least 0.7 m²/g such as, e.g., 1 m²/g. In certain uses the specificsurface area may range between about 0.7 m²/g and at least about 100m²/g and/or may be anything within this range and/or may be any mixtureof sizes within this range. For example, in certain embodiments, thesurface area may be about 0.7 m²/g, about 1 m²/g, about 1.5 m²/g, about2.0 m²/g, about 3.0 m²/g, about 5 m²/g, about 7 m²/g, about 10 m²/g,about 15 m²/g, about 20 m²/g, about 25 m²/g, about 35 m²/g, about 45m²/g, about 50 m²/g, about 75 m²/g, about 100 m²/g and above about 100m²/g, or combinations thereof. Such carriers having such suitablesurface areas may include, but are not limited to, mcc, fibrous materialor carbohydrates including cellulose (including hemicellulose,celluloses with different crystallinities and structures (e.g., varyingstructures including solid fibers, and addition or including fibers orthe like in various structures such as web-like structures and/or otherstructures), including naturally occurring celluloses includingCladophora sp. Algae cellulose or the like), dextran, agarose, agar,pectin, alginate, xanthan, chitosan, starch (including potato starch,shoti starch) etc. and/or mixtures thereof.

More specifically, nicotine may be sorbed on microcrystalline cellulose.

In general, the mean particle size of the cellulose such as e.g.microcrystalline cellulose is e.g., at the most about 500 μm, at themost about 450 μm, at the most about 300 μm, or at the most about 200μm, or from about 5 to about 500 μm, from 10 to about 500 μm, from 15 toabout 500 μm, from about 20 to about 500 μm, from about 30 to about 500μm, from about 40 to about 500 μm, from about 10 to about 400 μm, fromabout 20 to about 400 μm, from about 30 to about 400 μm, from about 40to about 400 μm, from about 30 to about 300 μm, from about 40 to about300 μm, from about 50 to about 250 μm, from about 50 to about 200 μm orfrom about 75 to about 200 μM.

However, as described hereinbefore the problem the present inventionaddresses is that the commercially qualities available have a particlesize that is too small in order to enable a retention of the snuffcomposition when it is placed in e.g. a bag made of gauze. Accordingly,the present invention deals with the specific situation where thecellulose quality that is suitable for sorbing and/or retaining nicotinehas a particle size of at the most 200 μm, such as, e.g., from about 5to about 200 μm, from 10 to about 200 μm, from 15 to about 200 μm, fromabout 20 to about 200 μm, from about 30 to about 200 μm, from about 40to about 200 μm, from about 50 to about 200 μm, or from about 75 toabout 200 μm.

In a preferred aspect, the mean particle size is in a range of fromabout 15 to about 250 μm such as from about 20 to about 200 μM. In theexamples herein a quality of cellulose such as, e.g., microcrystallinecellulose having a mean particle size of 180 μM has proved to bewell-suited for the present purpose.

However, as described above, there are no commercially availablepharmaceutically acceptable cellulose qualities that have a meanparticle size larger than 180 μm and this mean particle size is too low,when a snuff composition is packaged in e.g. pouches of gauze or othermaterial with openings having a size of about 200 μm. Accordingly, thepresent inventors have developed a method, which simultaneously loadsthe cellulose with nicotine and agglomerates the particles. In order toachieve a satisfactory result, the present inventors have found thatboth loading and agglomeration must take place in one and the sameprocess and using the same nicotine-containing solution for loading ofthe nicotine into the voids or pores of the cellulose and foragglomerating the particles. In this manner the present inventors havefound that it is possible both to obtain a desired load of nicotine intothe cellulose material and to obtain a suitable increase in particlesize. The resulting mean particle size is from about 200 μm to about 500μm, notably from about 200 μm to about 300 μm. Moreover, the presentinventors have found that use of a high-shear mixer is important for theloading and agglomeration process. The two knifes present in ahigh-shear mixer enable a uniform load as well as a controlled build-upin particle size. The liquid flow, temperature, speed rate etc. areadjustable parameters and depend on the size of the equipment. Once aperson skilled in the art has established suitable settings for one typeof apparatus, he will be able to adjust these settings to otherapparatuses.

The solvent for nicotine is preferably a volatile solvent such as, e.g.,an alcohol, preferably ethanol. The best results are achieved when thesolvent is used in a substantially anhydrous (or only with minor amountsof water) quality such as, e.g., 99% or 99.5% ethanol.

The loading and agglomerating solution normally contains from about 5 toabout 25% v/v nicotine, dependent on the specific nicotine employed.Thus, if a nicotine salt or complex is employed, the concentration maybe even higher provided that it does not exceed the solubility of thenicotine salt or complex in the liquid.

It is important that the process is carried out in a sufficient time toload the cellulose with nicotine and to agglomerate the particles;however, if the process time is too long, the agglomeration may beuncontrollable (i.e. much larger particles are formed) or irregularitieswith respect to nicotine may be observed. Accordingly, a suitableprocess time is from about 1 min to about 30 min for the preparation offrom about 1 to about 10 kg of the nicotine-cellulose combination.Moreover, it is important that the drying of the wetted combination isrelatively fast and without any external heating.

In a preferred embodiment a snuff composition according to the inventioncontains nicotine as a nicotine-microcrystalline cellulose carriercomplex in which said nicotine is at least partly sorbed onmicrocrystalline cellulose and/or is at least partially absorbed intothe carrier and/or is at least partially adsorbed onto the carrier(e.g., cellulose or microcrystalline cellulose), or mixtures thereof.Such interaction is completely or nearly completely reversible.

Hence, in certain specific embodiments nicotine is sorbed onmicrocrystalline cellulose, absorbed into the mcc and/or adsorbed ontothe cellulose (e.g. mcc), and/or combinations thereof.

The cellulose carrier (e.g., but not limited to microcrystallinecellulose and/or other naturally-occurring cellulose) is at leastpartially porous. This porosity may be due, for example but not limitedto, the structure of the carrier, for example, branched, fibrous, orweblike structures may have pores. Ranges of pore sizes include but arenot limited to pore volumes of about 0.01 cm³/g and include, but are notnecessarily limited to pore volume ranges of from about 0.003 cm³/g orless to about 0.025 cm³/g, to about or greater than 0.60 cm³/g.

In general, the nicotine carrier complex or nicotine carrier adduct ispresent in a snuff composition of the invention in a concentration of atleast about 2% w/w such as in a range from about 2% w/w to about 98%w/w, from about 2% to about 96% w/w, from about 2% w/w to about 95% w/w,from about 3% w/w to about 90% w/w, from about 4 w/w to about 85% w/w,from about 5% w/w to about 80% w/w, from about 5% w/w to about 75% w/w,from about 5% w/w to about 70% w/w, or from about 7.5% w/w to about 65%w/w.

The amount of nicotine sorbed, for example absorbed into and/or adsorbedonto to carrier can be up to 50% or more of the total weight of thecomposition. Ranges of the amount of nicotine sorbed onto the carrier inthe present invention range for less than about 1% of the total weightof the composition to more than about 50% of the composition, includingall amounts within this range. While applicants do not intend theinvention to be bound by theory, it is believed at the time of preparingthis application that the maximum amount of nicotine that can be sorbedonto and/or into the carrier, thereby affecting the amount, for examplethe percent nicotine by weight of the total composition (e.g., themaximum percentage) is affected by properties of the carrier, includingbut not limited to the structure of the carrier, the porosity of thecarrier, and the surface area of the carrier.

The concentration of the nicotine carrier complex or nicotine carrieradduct in a composition of the invention is present in a concentrationsuch as, e.g., from about 80% w/w to about 98% w/w, such as, e.g., fromabout 85% w/w to about 98% w/w, from about 90% w/w to about 98% w/w,from about 92% w/w to about 98% w/w, from about 93% w/w to about 97% w/wor from about 94% w/w to about 96% w/w.

The carrier may be capable of forming a complex with nicotine such as,e.g., in the case that the carrier compound is an ion-exchange compoundincluding polacrilex.

Concentrations and Amounts of Nicotine

As mentioned above, nicotine may be present in any suitable form.Normally, nicotine is selected from the group consisting of nicotinebase, nicotine hydrochloride, nicotine dihydrochloride, nicotinemonotartrate, nicotine bitartrate, nicotine sulfate, nicotine zincchloride such as nicotine zinc chloride monohydrate and nicotinesalicylate. In a preferred aspect, nicotine is in its free base form,which easily can be sorbed on a cellulose to form a microcrystallinecellulose-nicotine carrier complex or carrier adduct.

Normally, nicotine (calculated as the free base) is present in acomposition in a concentration of at least about 0.1% w/w such as in arange from about 0.1% w/w to about 50% w/w such as, e.g., from about0.5% w/w to about 45% w/w, from about 1.0% w/w to about 40% w/w, fromabout 1.5% w/w to about 35% w/w, from about 2% w/w to about 30% w/w,from about 2.5% w/w to about 25% w/w, from about 2.5% w/w to about 20%w/w, from about 3% w/w to about 15% w/w.

Moreover, a snuff composition according to the invention may containnicotine in a concentration from about 0.1% w/w to about 10% w/w, suchas, e.g., from about from about 0.1% w/w to about 8% w/w, from about0.1% w/w to about 6% w/w, from about 0.1% w/w to about 4% w/w, fromabout 0.1% w/w to about 2% w/w, from about 0.1% w/w to about 1.5% w/w,from about 0.2% w/w to about 1.0% w/w or from about 0.2% w/w to about0.8% w/w, calculated as free base.

In a snuff composition of the invention the nicotine is typicallypresent in a concentration from about 0.1% w/w to about 5% w/w, such as,e.g., from about from about 0.1% w/w to about 4% w/w, from about 0.1%w/w to about 3% w/w, from about 0.1% w/w to about 2% w/w, from about0.1% w/w to about 1% w/w, from about 0.1% w/w to about 0.75% w/w, fromabout 0.2% w/w to about 0.5% w/w or from about 0.2% w/w to about 0.4%w/w, calculated as free base.

As mentioned above, the nicotine is present in the form of anicotine-cellulose combination. In general, this combination is presentin a concentration of from about 5% to about 100% such as, e.g., fromabout 10 to about 100%, from about 5% to about 50% or, alternatively,from about 45% to about 100%. The choice of suitable concentrationdepends on the load of nicotine in the nicotine-cellulose combinationand the dosage of nicotine in a single pouch or bag. If the load isrelatively high, then the concentration of the combination may be lowerthan if the load is relatively low. In those cases, where e.g. Avicel®or a similar cellulose quality is used, a concentration of thecombination in the composition is generally from about 80% w/w to about98% w/w, such as, e.g., from about 85% w/w to about 98% w/w, from about90% w/w to about 98% w/w, from about 92% w/w to about 98% w/w, fromabout 93% w/w to about 97% w/w or from about 94% w/w to about 96% w/w.

The concentration of nicotine (or the pharmaceutically acceptable salt,complex or solvate thereof) in the combination is at the most 70% w/wsuch as, e.g., at the most 60% w/w, at the most 50% w/w, at the most 45%w/w. The content of nicotine must not be so high that the combination(which is in powder form) “sweats”, so that nicotine desorbs, evaporatesor otherwise disappears from the combination. Accordingly, the load ofnicotine in the combination is dependent on the particular celluloseemployed. If the surface area of the cellulose material is relativelyhigh, then a larger amount of nicotine can be contained therein in astable manner during a suitable period of time, whereas a cellulosehaving a smaller surface area normally is indicative for a lowercapacity to load nicotine in a suitable manner with respect tostability.

For most cellulose qualities, the concentration of nicotine in thenicotine-cellulose combination is at the most about 45% w/w, such as,e.g., at the most about 40% w/w, at the most about 35% w/w, at the mostabout 30% w/w, at the most about 25% w/w, at the most about 20% w/w, atthe most about 15% w/w, at the most about 12.5% w/w, at the most about10% w/w, at the most about 9.5% w/w, at the most about 9% w/w, at themost about 8.5% w/w or at the most about 8% w/w, and the concentrationbeing calculated as the nicotine base.

Typically a nicotine-cellulose combination has a concentration ofnicotine or the pharmaceutically acceptable salt, complex or solvatethereof in the combination is at the most about 7.5% w/w such as, e.g.,at the most about 7% w/w, at the most about 6.5% w/w, at the most about6% w/w, at the most about 5.5% w/w, at the most about 5% w/w, at themost about 4.5% w/w, at the most about 4% w/w, at the most about 3% w/w,at the most about 2% w/w or at the most about 1% w/w, and theconcentration being calculated as the nicotine base.

The amount of the nicotine compound (calculated as the free base) in acomposition of the inventions is generally from about 0.5 mg to about 10mg such as, e.g., from about 1 mg to about 8 mg, from about 1.5 mg toabout 7.5 mg, from about 2 mg to about 5 mg, from about 2.5 mg to about5 mg, from about 3 to about 10 mg, from about 3 to about 7.5 mg or fromabout 3 mg to about 5 mg such as, e.g., about 1.5 mg, about 2 mg, about2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 5 mg or about 6 mg,as calculated as free nicotine base. In particular a dosage of 2 mg, 3mg, 4 mg and 6 mg is of commercial interest.

Buffering Agents

A composition according to the invention may also contain one or morebuffering agents. It is generally known that a slightly alkalinereaction (between 7 and 8) in the oral cavity enhances the absorption ofnicotine. Accordingly, it may be and advantage to incorporate a buffersubstance in the composition such that a slightly alkaline reaction isprovided. Especially compositions for release of the nicotine in theoral cavity can advantageously contain a buffer substance, i.e.compositions like snuff compositions.

Suitable buffering agents are typically those selected from the groupconsisting of acetates, glycinates, phosphates, glycerophosphates,citrates such as citrates of alkaline metals, carbonates, and hydrogencarbonates, and borates, or mixtures thereof. Especially, a carbonate, ahydrogen carbonate or a phosphate including a triphosphate is suitableas a buffer agent.

If present the one or more buffering agents are present in aconcentration from about 0.5% w/w to about 5% w/w, such as, e.g., fromabout 0.75% w/w to about 4%, w/w, from about 0.75% w/w to about 3%, w/wor from about 1% w/w to about 2%, w/w.

The concentration of the one or more buffering agents may be from about0.1% w/w to about 5% w/w, such as, e.g., from about 0.2% w/w to about 4%w/w, from about 0.3% w/w to about 4% w/w, from about 0.4% w/w to about3% w/w, from about 0.5% w/w to about 2% w/w, from about 0.6% w/w toabout 1% w/w or from about 0.7% w/w to about 0.9% w/w such as about 0.8%w/w.

Sweeteners—Flavouring Agents

In order to improve the sensory properties of the composition accordingto the invention one or more sweeteners or texture improves may beadded, such as sugar alcohols including xylitol, sorbitol, maltitoland/or isomalt, or artificial sweeteners such as e.g. aspartame,acesulfame or saccharin.

The concentration of the one or more sweeteners, if present, is normallyat least about 0.05% such as, e.g. from about 0.075% w/w to about 5% w/wor from about 5% to about 35% w/w, such as, e.g., from about 10% w/w toabout 35% w/w, from about 15% w/w to about 35% w/w or from about 20% w/wto about 30% w/w. In an interesting embodiment the one or moresweeteners are present in a concentration from about 0.01% w/w to about0.2% w/w, such as, e.g., from about 0.01% w/w to about 0.15% w/w, fromabout 0.02% w/w to about 0.12% w/w, from about 0.03% w/w to about 0.11%w/w, from about 0.04% w/w to about 0.1% w/w, from about 0.05% w/w toabout 0.1% w/w, from about 0.06% w/w to about 0.1% w/w or from about0.07% w/w to about 0.09% w/w such as about 0.08% w/w. As demonstrated inthe examples herein a concentration of the one or more artificialsweeteners of about 0.08% gives good sensoric acceptance.

In order to improve the organoleptic properties of a compositionaccording to the invention, the composition may include one or moreflavouring agents, such as, e.g., menthol flavour, eucalyptus, mintflavour and/or L-menthol, normally present (total concentration offlavouring agents) in a concentration of from about 0.5% w/w to about12% w/w, from about 1% w/w to about 10% w/w, from about 1.5% w/w toabout 9% w/w or from about 2% w/w to about 8% w/w.

The flavour may be mint flavour and the concentration of the one or moreflavouring agents is from about 1% w/w to about 15% w/w, such as, e.g.,from about 1% w/w to about 10% w/w, from about 1.5% w/w to about 8% w/w,from about 2% w/w to about 6% w/w or from about 3% w/w to about 5% w/wsuch as about 4% w/w. In a specific embodiment, the concentration of theone or more flavouring agents is about 4% w/w.

It is well-known that nicotine is subject to oxidation and accordingly,it may be advantageous to incorporate one or more anti-oxidants, suchas, e.g., ascorbyl palmitate and/or sodium ascorbate, in a compositionaccording to the invention.

The one or more anti-oxidants may be present in a concentration of fromabout 0.4% w/w to about 2.4% w/w, such as, e.g., from about 0.5% w/w toabout 2.2% w/w, from about 0.6% w/w to about 2% w/w, from about 0.7% w/wto about 1.8% w/w or from about 0.8% w/w to about 1.6% w/w.

Specific Embodiments

In specific embodiments the invention relates to

A snuff composition comprising

i) a carrier,

ii) nicotine, or a pharmaceutically acceptable salt, solvate, complex,or derivative thereof,

wherein at least about 30% w/w of the total content of nicotine isreleased within 30 minutes when said composition is subjected to an invitro dissolution test.

A snuff composition comprising

i) a nicotine-cellulose combination

ii) one or more pharmaceutically acceptable excipients or additive thecomposition being encapsulated in a bag, pouch or membrane material.

A snuff composition comprising

i) a nicotine-cellulose combination containing from about 0.5 to about10 mg of nicotine

ii) a flavoring agent

iii) a sweetener

the composition being encapsulated in a bag, pouch or membrane material.

A snuff composition comprising

i) a nicotine-cellulose combination containing from about 0.5 to about10 mg of nicotine

ii) a flavoring agent

iii) a sweetener

iv) an antioxidant

the composition being encapsulated in a bag, pouch or membrane material.

A method of administering a snuff composition with a high release ratecomprising the step of:

delivering a snuff composition comprising a carrier combined withnicotine, or a pharmaceutically acceptable salt, solvate, complex, orderivative thereof, wherein at least about 30% w/w of the total contentof nicotine is released within 30 minutes when said composition issubjected to an in vitro dissolution test.

A method of making a snuff composition with a high release rate,comprising the step of:

combining nicotine, or a pharmaceutically acceptable salt, solvate,complex, or derivative thereof, with a carrier, wherein at least about30% w/w of the total content of nicotine is released within 30 minuteswhen said composition is subjected to an in vitro dissolution test.

All particulars and details mentioned above relating to the main aspectin general apply mutatis mutandis to the above mentioned specificembodiments.

The invention is further illustrated in the following figures andnon-limiting examples.

LEGENDS TO THE FIGURES

FIG. 1 shows an assembly of the dialysis membrane to the siliconehose—the assembly is a part of the dissolution testing apparatus fortesting of snuff compositions

FIG. 2 shows an overview of tubing routes in the dissolution testing ofsnuff compositions

FIG. 3 shows a sample tube for dissolution testing of snuff compositions

FIGS. 4 and 5 show in vitro release profile for snuff compositionsdescribed in Example 2

FIGS. 6 and 7 show the in vivo uptake of nicotine from snuffcompositions described in Example 3.

FIG. 8 show the plasma concentration versus time for the experimentdescribed in Example 5 comparing Nicorette® chewing gum (4 mg) with asnuff composition of the invention containing 5 mg of nicotine

METHODS In Vitro Dissolution Test

The snuff compositions according to the invention are normally tested tofulfill specific requirements with respect to in vitro release ofnicotine. A suitable in vitro test depends on the specific compositionin question. In general, a person skilled in the art will find guidanceas to how to choose a relevant dissolution test for a specificcomposition in the official monographs such as, e.g., the EuropeanPharmacopoeia. Below are described suitable dissolution tests in case ofsnuff compositions.

Snuff

The following dissolution method for testing of the release of nicotinefrom snuff compositions was used.

The method describes in-vitro release of nicotine from snuff using UVdetection. The released nicotine diffuses through a dialysis membraneinto a stream of tempered phosphate buffer.

Equipment

UV spectrophotometer HP 8453 or equivalent Sipper HP Peristaltic pump orequivalent Secondary pump Flexicon PF5 or equivalent Magnetic stirrerLabasco or equivalent Water bath Gant W14 or equivalentInstrument Settings

UV spectrophotometer Wavelengths 244.259 and 274 nm Flow cell 1.000 cmWaterbath Temperature 37° C. Secondary pump Pump flow 30 rpm Magneticstirrer Rotation Gentle stirMaterialsDialysis membrane, Spectra/Por®, MWCO 500,Silicon tubing, i.d. 6 mmSample Tube250 ml beakerReagentsChemicals & Solvents:Purified water, H₂OSodium Hydroxide, min 98%, NaOHSodium Dihydrogen Phosphate Monohydrat, min 98%, NaH₂PO₄.H₂OReference Material:Nicotine bitartrate dihydrate, standardSolutions:5 M Sodium hydroxidePhosphate buffer, pH 6.8ProcedureApparatus Assembly

Cut two pieces of silicon hoses, 150 and 35 cm long. Insert a 3 cm longhard plastic hose (o.d. 7 mm) in one end of the two ‘blood vessels’ forsupport. Cut a piece of dialysis membrane and pre-treat according tomanufacturer. Thread the membrane through two 2.5 cm long silicon hosepieces (i.d. 6 mm). The supported ends of the blood vessels should beinserted approximately 3 cm into the membrane and secured with the twosmall silicon rings (See FIG. 1).

Add 250 ml phosphate buffer [6] to the 250 ml beaker and add a magneticbar. Place it in the water bath and start the heating and rotation.Connect the silicone hose to the secondary pump and place the longestpart to the beaker. Place a pipette tip (1 ml) into the shorter end towork as a pressure restrictor. The hole in the tip may be expanded inorder to adjust the back pressure. Prime the tubing with buffer.

Place the two tubings from the flow cell in the beaker. (See FIG. 2) andobtain a blank measurement.

Stop the flow and fold the membrane on the middle. Use a piece of paperto slide the membrane into the sample tube as far down as possible.Start the pump and carefully insert the snuff bag halfway down thesample tube between the membranes (see FIG. 3). Add phosphate buffer [2]to the tube enough to cover the sample. Place the sample tube in thewater bath and start the analysis.

Sampling

Blank: Measure blank before the membrane is placed into the sample tube.

Sampling: Withdraw sample online every fifth minute for 30 minutes usingthe sipper. Measure the absorbance at 244, 259 and 274 nm.

Standards: Pump S1-S3 into the flow cell after the sampling sequence.Measure the absorbance at 244, 259 and 274 nm.

Evaluation

The concentrations of nicotine in the samples are calculated.

As an alternative method, USP basket method (in vitro dissolution oftablets) can be used employing 500 ml water as dissolution medium.

REFERENCE EXAMPLES Reference Example 1 Snuff Bag Compositions E, F, G,H, I and J

Nicotine was sorbed onto microcrystalline cellulose (MCC) as describedin WO 2004/056363. Accordingly, in the present example 2.40 ml nicotinewas dissolved in 25 ml ethanol (99.5%). 47.6 g MCC of type PH-102 wasloaded into a high-speed mixer and the nicotine was slowly added. Aftervacuum drying of the obtained wetted mass a fine-grained, white powderof nicotine-microcrystalline cellulose carrier complex was obtained.

Nicotine was sorbed onto microcrystalline cellulose (MCC) to obtainnicotine-microcrystalline cellulose carrier complexes essentially asdescribed above. The obtained nicotine-microcrystalline cellulosecarrier complexes were mixed with the remaining ingredients to obtainthe compositions E, F, G, H, I and J stated in the following table:

Com- Com- Com- Com- Com- Com- posi- posi- posi- posi- posi- posi- COM-tion E tion F tion G tion H tion I tion J POSI- Quan- Quan- Quan- Quan-Quan- Quan- TION tity tity tity tity tity tity Ingre- (mg/ (mg/ (mg/(mg/ (mg/ (mg/ dient unit) unit) unit) unit) unit) unit) Nicotine 6.006.00 6.00 4.00 4.00 6.00 Micro- 138 137 137 139 139 135 crys- tallinecellulose Pepper- 6.00 6.00 6.00 6.00 6.00 6.00 mint powder flavourAcesul- 0.06 0.06 0.06 0.06 0.06 0.06 fame potas- sium Aspar- 0.06 0.060.06 0.06 0.06 0.06 tame powder Sodium — — — — — 1.20 car- bonate Sodium— 1.20 — 1.20 — 1.20 hydrogen car- bonate Sodium — — 1.20 — 1.20 —triphos- phate Target 150 150 150 150 150 150 Weight Meas- 9.47 9.0210.4- 8.95 10.3- 9.95 ured 10.8 10.5 pH, 5 g in 100 ml H2O In-vitro 2.62.6 2.6- 1.8 1.6- 3.0 release, 2.7 1.7 30 min (mg)* Meas- 5.9 6.0 6.0-4.2 3.8- 6.3 ured 6.3 4.2 assay

Nicotine was purchased from Siegfried, Switzerland, (batch no.03381006), Microcrystalline cellulose was purchased from FMC, Belgium(batch no. M301C), Peppermint powder flavour was purchased fromFirmenich, Switzerland (batch no. JP05040527), Acesulfame potassium waspurchased from L&P Food Ingredient, China (batch no. (ZD02035),Aspartame powder was purchased from NutraSweet, Switzerland (batch no.C000220), Sodium carbonate was purchased from Aldrich, Germany (batchno. A008729PI), Sodium hydrogen carbonate was purchased from Merck,Germany (batch no. K28409723047), Sodium triphosphate was purchased fromSigma, USA (supplied from Swedish Match Sweden).

150 mg of the compositions E-J, respectively, were filled into snuffbags made of a snuff bag material obtained from Swedish Match, Sweden(batch no. W-NR00217, RL-NR6). The snuff bag size used is similar to thepresent marketed dry snuff bags, i.e. as “Catch® dry”.

Reference Example 2 In Vitro Release from Snuff Bag Compositions E, F,G, H, I and J

Measurement of in vitro release rates of nicotine from snuff bags wereperformed using an in vitro dissolution test developed at Swedish Match,Stockholm, and utilizing a plastic flow-chamber in a tube with buffersolution combined with UV detection on a spectrophotometer at 260 nm.The details are mentioned above under the heading “In vitro dissolutiontest”.

The in vitro release of nicotine from compositions E-J in percentage ofthe total content of nicotine are stated in the table below:

COMPO- Compo- Compo- Compo- Compo- Compo- Compo- SITION sition E sitionF sition G sition H sition I sition J Nicotine 6.00 6.00 6.00 4.00 4.006.00 content (mg) In vitro 2.6 2.6 2.6-2.7 1.8 1.6-1.7 3.0 release, 30min (mg) Percentage 43% 43% 43-45% 45% 40-42% 50% of released nicotine

Furthermore, comparison studies of the in vitro release profiles ofnicotine from snuff bags containing snuff compositions according to thepresent invention and already marketed snuff bags were performed. InFIG. 4 the in vitro release profiles of nicotine from compositions F andH were compared with the in vitro release profiles of nicotine from thepresent marketed dry snuff bags “Catch® dry” and “general white” usingthe first of the above-mentioned in vitro release methods. FIG. 4illustrates the improved in vitro release of nicotine from snuffcompositions according to the present invention compared to both “Catch®dry” and “general white”: Snuff composition F which contains 6 mgnicotine releases significantly more nicotine than the already marketedproducts “Catch® dry” and “general white”. As the marketed products arenatural products information of the exact content of nicotine is notavailable, but it is disclosed that the weight is 1 gram or less, thenicotine content is 5-11 mg, the pH is 7.3-8.5 and the buffer content is1.5-3.5%.

In FIG. 5 the in vitro release rates of nicotine from snuff compositionsE, F and G containing 6 mg of nicotine and snuff compositions H and Icontaining 4 mg of nicotine, were compared to the in vitro release ratesof nicotine from “General” compositions 1, 2 and 3. Again, the snuffcompositions according to the present invention exhibit a better releaserelative to the total content of nicotine in the composition/product.

Reference Example 3 In Vivo Uptake of Nicotine from Snuff Bag ContainingComposition

A comparison study of the in vivo uptake of nicotine from the snuffproduct “General”, 4 mg Nicorette® chewing gum and a snuff bagcomprising composition J was performed. Composition J contained 0.8%sodium hydrogen carbonate and 0.8% sodium carbonate. Blood samples weretaken at 0, 5, 10, 15, 20, 30 and 40 minutes after application and theplasma concentrations of nicotine were determined by ABS laboratories,London, England. After addition of sodium hydroxide, the plasma sampleswere extracted with dichloroethane and nicotine was quantitativelydetermined by gas chromatography using a nitrogen/phosphorous detector.5-methyl cotinine was used to internally standardize the procedure. Thelimit of quantification is 0.5 ng/ml.

The results are shown in FIG. 6. For comparison reasons the in vivouptake of nicotine from the snuff product “General” was normalized to anicotine content of 6 mg. FIG. 6 shows that over a time period of 30minutes, the snuff bag containing composition J provides a plasma levelof nicotine exceeding those of both “General” and Nicorette® 4 mgnicotine chewing gum.

Furthermore, a pilot pharmacokinetic study (n=4) in which the in vivouptake of nicotine from snuff compositions G, J and I were compared tothe in vivo uptake from Nicorette® 4 mg chewing gum. The result shown inFIG. 7 illustrates that the in vivo uptake of nicotine from each ofthese snuff compositions is significantly better than from Nicorette® 4mg chewing gum.

Reference Example 4 Residual Amounts of Nicotine in Snuff BagsComprising Snuff Compositions G, I and J In Vitro vs. In Vivo

Snuff bags comprising either of compositions G, I or J were subjected toeither the above-mentioned in vitro dissolution test employing USPbasket apparatus or the above-mentioned pilot pharmacokinetic assay in30 minutes. Subsequently, the residual nicotine content in the snuffbags was investigated using a dissolution bath combined with aUV-detection on a spectrophotometer at 260 nm. The dissolution wasdetermined according to the dissolution method for tablets USP (basket)using 500 ml water as dissolution medium and a temperature of 37° C.

The results are shown in the following table:

Composition Composition Composition Snuff composition I G J Measurednicotine assay (mg) 3.8 6.3 6.3 Mean in vitro residual amount 1.9 3.63.3 nicotine after 30 minutes (n = 2) (mg) Mean in vitro residual amount50 57 52 nicotine after 30 minutes (n = 2) (%) Mean in vivo residualamount 1.98 3.06 2.84 nicotine after 30 minutes (n = 4) (mg) Mean invivo residual amount 52 49 45 nicotine after 30 minutes (n = 4) (%)Diversion in vitro vs in vivo −2 +8 +7 (% vs %)

It follows from the figures in the above table, that the residual amountof nicotine in the snuff bags after 30 minutes of in vitro dissolutiontest is between 50% and 57% of the initial content of nicotine, i.e.between 43% and 50% of the nicotine has been released in the in vitrodissolution test. It further follows that the residual amount ofnicotine in the snuff bags after 30 minutes of the in vivopharmacokinetic study, is between 45% and 50% of the initial content ofnicotine, i.e. between 45% and 50% of the nicotine has been absorbed inthe bloodstream.

Reference Example 5 Comparison of Nicorette 4 mg Gum with MCC-NicotineContaining Snuff Composition with 5 mg Nicotine

Single dose pharmacokinetics was studied in four subjects in comparisonto Nicorette 4 mg gum (FIG. 8). FIG. 8 shows the results from a singledose pharmacokinetic study in four subject comparing Nicorette® 4 mgchewing gum with a snuff composition containing MCC-nicotinecorresponding to 5 mg nicotine after oral application.

The bioavailability of nicotine from the nicotine snuff compositionappears higher that that seen for the Nicorette® composition even if thedifferent in dosage is taken into account.

The following example is included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples that follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLES Example 1 Loading Nicotine on a Cellulose and SimultaneousAgglomeration of the Particles

2.40 ml nicotine is dissolved in 25 ml ethanol (99.5%). 47.6 g MCC oftype PH-102 is loaded into a high-speed mixer and the nicotine solutionis slowly added with a flow in a range of from about 0.05 to about 10ml/min (the faster rotation, the faster addition of the solution) Whenall of the solution is added, the mixer is run for a time period of atthe most 5 min. The obtained wetted material is subject to drying invacuum and a, white powder of nicotine-microcrystalline cellulosecombination is obtained. The mean particle size of the combination isanalysed by size analysis or the like.

REFERENCES

All patents and publications mentioned in the specification areindicative of the levels of those skilled in the art to which theinvention pertains. All patents and publications are herein incorporatedby reference to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by reference.

Although the present invention and its advantages have been described indetail, it should be understood that various changes, substitutions andalterations can be made herein without departing from the spirit andscope of the invention as defined by the appended claims. Moreover, thescope of the present application is not intended to be limited to theparticular embodiments of the process, machine, manufacture, andcomposition of matter, means, methods and steps described in thespecification. As one of ordinary skill in the art will readilyappreciate from the disclosure of the present invention, processes,machines, manufacture, compositions of matter, means, methods, or steps,presently existing or later to be developed that perform substantiallythe same function or achieve substantially the same result as thecorresponding embodiments described herein may be utilized according tothe present invention. Accordingly, the appended claims are intended toinclude within their scope such processes, machines, manufacture,compositions of matter, means, methods, or steps.

Specific Embodiments Include the Following Items

1. A method for the preparation of a nicotine-cellulose combination, themethod comprising

i) dissolving a nicotine in a solvent,

ii) mixing the thus obtained solution with a cellulose having a meanparticle size of less than about 180 μm in a high-shear mixer tosimultaneous load the nicotine on the cellulose and agglomerate theparticles to obtain a nicotine-cellulose combination having a meanparticle size of from about 200 μm to about 500 μm and with a load ofnicotine of at least 5% v/w.

2. A method according to item 1, wherein the solvent is a volatilesolvent.

3. A method according to item 1, wherein the solvent is an alcohol.

4. A method according to any of the preceding items, wherein the solventis ethanol in a concentration of at least 95% v/v such as, e.g. at least98%, at least 99% or about 99.5% v/v.

5. A method according to any of the preceding items carried out in ahigh-shear mixer.

6. A method according to any of the preceding items, wherein the mixingis continued for at the most 1 hour/kg cellulose employed.

7. A method according to any of the preceding item, wherein thetemperature in the mixer is at the most about 30-40° C.

8. A method according to any of the preceding items, wherein at the most10% such as at the most 5% of the nicotine-cellulose combinationobtained has a particle size of 200 μm or less.

9. A method according to any of the preceding items further comprisingdrying the mixture resulting from step ii) by means of vacuum drying atthe most at room temperature.

10. Use of a nicotine-cellulose combination as defined in any of items1-9 for the preparation of a snuff composition for achievement of a fastonset of action of nicotine after application of the snuff compositionto the oral cavity of a subject.

11. Use according to item 10, wherein the composition has a high releaserate so that when subjected to an in vitro dissolution test about 45% ormore of the total content of nicotine is released within 30 minutes.

12. Use according to item 10 or 11, wherein the onset is within 5minutes such as, e.g. within 4 minutes, within 3 minutes, within 2minutes or within 1.5 minutes after application of composition betweenthe lip and the teeth of a subject.

13. Use according to any of items 10-12, wherein the nicotine-cellulosecombination is enclosed in a membrane material.

14. Use according to item 13, wherein the membrane is a natural,synthetic, semi-synthetic hydrophilic or hydrophobic membrane.

15. Use according to item 12 or 13, wherein the membrane is made fromone or more biocompatible and physiologically acceptable polymericmaterial.

16. Use according to any of items 12-15, wherein the membrane materialis selected from the group consisting of cellulose acetate andderivatives thereof, carboxymethyl cellulose, polycellulose ester, othercellulose derivatives including ethylcellulose, propylcellulose,polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylacetate, polymers of methacrylates and acrylates, natural rubber,polycarbonate, polyethylene terephthalate, polyester, polyamide andnylon.

17. Use according to any of items 10-16, wherein the nicotine isnicotine (free base) or a pharmaceutically acceptable salt, solvate,complex, or derivative thereof.

18. Use according to any of items 10-17, wherein about 50% or more suchas, e.g., about 60% or more, about 70% or more or about 75% or more ofthe total content of nicotine is released within 30 minutes whensubjecting the composition to an in vitro dissolution test.

19. Use according to any of items 10-18, wherein the composition—whensubjected to an in vitro dissolution test—releases about 45% or moresuch as, e.g., 50% or more within 20 minutes.

20. Use according to any of items 10-19, wherein the composition—whensubjected to an in vitro dissolution test—releases about 20% or moresuch as, e.g., about 25% or more within 10 minutes.

21. Use according to any of items 10-20 for buccal administration.

22. Use according to any of items 10-21, wherein the in vivo release ofnicotine 30 minutes after buccal administration corresponds to at leastabout 30% of the total content of nicotine in the snuff.

23. Use according to any of items 10-22, wherein the in vivo release ofnicotine 30 minutes after buccal administration corresponds to at leastabout 35% such as, e.g., at least about 40%, at least about 42%, atleast about 45%, at least about 50%, at least about 55%, at least about60%, at least about 65%, at least about 70% or at least about 75% w/w ofthe total content of nicotine in the snuff.

24. Use according to any of items 10-23, wherein the cellulose of thenicotine-cellulose combination comprises internal voids and/or pores.

25. Use according to item 24, wherein said voids and/or pores at leastpartially comprise said nicotine.

26. Use according to any of items 10-25, wherein the cellulose is acellulose derived from a plant, an algae, a bacterium, a fungi, orcombinations thereof

27. Use according to any of items 10-26, wherein the cellulose has asurface area of at least 0.7 m²/g.

28. Use according to any of items 10-27, wherein the cellulose is acrystalline cellulose including a microcrystalline cellulose.

29. Use according to any of items 10-28, wherein said cellulose is amicrocrystalline cellulose, which is selected from the group consistingof AVICEL® grades PH-100, PH-102, PH-103, PH-105, PH-112, PH-113,PH-200, PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20 and EMOCEL®grades 50M and 90M, and the like, and mixtures thereof.

30. Use according to item 28 or 29, wherein said microcrystallinecellulose is synthetic or semi-synthetic celluloses, or it is derivedfrom natural celluloses.

31. Use according to any of items 10-30, wherein the mean particle sizeof the cellulose is in a range of from about 15 to about 250 μm.

32. Use according to any of items 10-31, wherein nicotine is at leastpartly sorbed on the cellulose.

33. Use according to any of items 10-32, wherein nicotine is present inthe composition in a concentration from about 0.1% w/w to about 10% w/w,such as, e.g., from about from about 0.1% w/w to about 8% w/w, fromabout 0.1% w/w to about 6% w/w, from about 0.1% w/w to about 4% w/w,from about 0.1% w/w to about 2% w/w, from about 0.1% w/w to about 1.5%w/w, from about 0.2% w/w to about 1.0% w/w or from about 0.2% w/w toabout 0.8% w/w, calculated as free base.

34. Use according to any of items 10-33, wherein the nicotine-cellulosecombination is present in a concentration from about from about 80% w/wto about 98% w/w, such as, e.g., from about 85% w/w to about 98% w/w,from about 90% w/w to about 98% w/w, from about 92% w/w to about 98%w/w, from about 93% w/w to about 97% w/w or from about 94% w/w to about96% w/w.

35. Use according to any of items 10-35, wherein the composition furthercomprises one or more sweeteners in a concentration from about 0.01% w/wto about 0.2% w/w, such as, e.g., from about 0.01% w/w to about 0.15%w/w, from about 0.02% w/w to about 0.12% w/w, from about 0.03% w/w toabout 0.11% w/w, from about 0.04% w/w to about 0.1% w/w, from about0.05% w/w to about 0.1% w/w, from about 0.06% w/w to about 0.1% w/w orfrom about 0.07% w/w to about 0.09% w/w.

36. Use according to item 35, wherein the concentration of the one ormore sweeteners in the composition is about 0.08% w/w.

37. Use according to any of items 10-36, wherein the composition furthercomprises one or more flavouring agents such as mint flavour.

38. Use according to item 37, wherein the concentration of the one ormore flavouring agents in the composition is from about 1% w/w to about15% w/w, such as, e.g., from about 1% w/w to about 10% w/w, from about1.5% w/w to about 8% w/w, from about 2% w/w to about 6% w/w or fromabout 3% w/w to about 5% w/w.

39. Use according to item 38, wherein the concentration of the one ormore flavouring agents in the composition is about 4% w/w.

40. Use according to any of items 10-39, wherein the composition furthercomprises one or more buffering agents such as, e.g., a carbonate, ahydrogen carbonate or a phosphate including a triphosphate.

41. Use according to item 40, wherein the concentration of the one ormore buffering agents in the composition is from about 0.1% w/w to about5% w/w, such as, e.g., from about 0.2% w/w to about 4% w/w, from about0.3% w/w to about 4% w/w, from about 0.4% w/w to about 3% w/w, fromabout 0.5% w/w to about 2% w/w, from about 0.6% w/w to about 1% w/w orfrom about 0.7% w/w to about 0.9% w/w.

42. Use according to item 41, wherein the concentration of the one ormore buffering agents in the composition is about 0.8% w/w.

43. Use according to any of items 10-42, wherein the composition furthercomprises one or more anti-oxidants in a concentration of from about0.4% w/w to about 2.4% w/w, such as, e.g., from about 0.5% w/w to about2.2% w/w, from about 0.6% w/w to about 2% w/w, from about 0.7% w/w toabout 1.8% w/w or from about 0.8% w/w to about 1.6% w/w.

44. A snuff composition comprising a nicotine-cellulose combination andone or more acceptable excipients, wherein the nicotine-cellulosecombination has a mean particle size of 200 μm or more such as, e.g., ina range of from about 250 van to about 500 μm.

45. A snuff composition according to item 44, wherein thecomposition—when subjected to an in vitro dissolution test as describedherein for 30 minutes about 45% or more of the total content of nicotineis released.

46. A snuff composition according to item 44 or 45, wherein thenicotine-cellulose combination is enclosed in a membrane material.

47. A snuff composition according to item 46, wherein the membrane is anatural, synthetic, semi-synthetic hydrophilic or hydrophobic membrane.

48. A snuff composition according to item 46 or 47, wherein the membraneis made from one or more biocompatible and physiologically acceptablepolymeric material.

49. A snuff composition according to any of items 46-48, wherein themembrane material is selected from the group consisting of celluloseacetate and derivatives thereof, carboxymethyl cellulose, polycelluloseester, other cellulose derivatives including ethylcellulose,propylcellulose, polyethylene, polypropylene, polystyrene, polyvinylchloride, polyvinyl acetate, polymers of methacrylates and acrylates,natural rubber, polycarbonate, polyethylene terephthalate, polyester,polyamide and nylon.

50. A snuff composition according to any of items 45-49, wherein thenicotine is nicotine (free base) or a pharmaceutically acceptable salt,solvate, complex, or derivative thereof.

51. A snuff composition according to any of items 45-50, wherein about50% or more such as, e.g., about 60% or more, about 70% or more or about75% or more of the total content of nicotine is released within 30minutes when subjecting the composition to an in vitro dissolution test.

52. A snuff composition according to any of items 45-51, wherein thecomposition—when subjected to an in vitro dissolution test—releasesabout 45% or more such as, e.g., 50% or more within 20 minutes.

53. A snuff composition according to any of items 45-52, wherein thecomposition—when subjected to an in vitro dissolution test—releasesabout 20% or more such as, e.g., about 25% or more within 10 minutes.

54. A snuff composition according to any of items 45-53 for buccaladministration.

55. A snuff composition according to any of items 45-54, wherein the invivo release of nicotine 30 minutes after buccal administrationcorresponds to at least about 30% of the total content of nicotine inthe snuff.

56. A snuff composition according to any of items 45-55, wherein the invivo release of nicotine 30 minutes after buccal administrationcorresponds to at least about 35% such as, e.g., at least about 40%, atleast about 42%, at least about 45%, at least about 50%, at least about55%, at least about 60%, at least about 65%, at least about 70% or atleast about 75% w/w of the total content of nicotine in the snuff.

57. A snuff composition according to any of items 45-56, wherein thecellulose of the nicotine-cellulose combination comprises internal voidsand/or pores.

58. A snuff composition according to item 57, wherein said voids and/orpores at least partially comprise said nicotine.

59. A snuff composition according to any of items 45-58, wherein thecellulose is a cellulose derived from a plant, an algae, a bacterium, afungi, or combinations thereof

60. A snuff composition according to any of items 45-59, wherein thecellulose has a surface area of at least 0.7 m²/g.

61. A snuff composition according to any of items 45-60, wherein thecellulose is a crystalline cellulose including a microcrystallinecellulose.

62. A snuff composition according to any of items 45-61, wherein saidcellulose is a microcrystalline cellulose, which is selected from thegroup consisting of AVICEL® grades PH-100, PH-102, PH-103, PH-105,PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL® grades 101, 102, 12, 20and EMOCEL® grades 50M and 90M, and the like, and mixtures thereof.

63. A snuff composition according to item 61 or 62, wherein saidmicrocrystalline cellulose is synthetic or semi-synthetic celluloses, orit is derived from natural celluloses.

64. A snuff composition according to any of items 45-63, wherein themean particle size of the cellulose is in a range of from about 15 toabout 250 μm.

65. A snuff composition according to any of items 45-64, whereinnicotine is at least partly sorbed on the cellulose.

66. A snuff composition according to any of items 45-65, whereinnicotine is present in the composition in a concentration from about0.1% w/w to about 10% w/w, such as, e.g., from about from about 0.1% w/wto about 8% w/w, from about 0.1% w/w to about 6% w/w, from about 0.1%w/w to about 4% w/w, from about 0.1% w/w to about 2% w/w, from about0.1% w/w to about 1.5% w/w, from about 0.2% w/w to about 1.0% w/w orfrom about 0.2% w/w to about 0.8% w/w, calculated as free base.

67. A snuff composition according to any of items 45-66, wherein thenicotine-cellulose combination is present in a concentration from aboutfrom about 80% w/w to about 98% w/w, such as, e.g., from about 85% w/wto about 98% w/w, from about 90% w/w to about 98% w/w, from about 92%w/w to about 98% w/w, from about 93% w/w to about 97% w/w or from about94% w/w to about 96% w/w.

68. A snuff composition according to any of items 45-67, wherein thecomposition further comprises one or more sweeteners in a concentrationfrom about 0.01% w/w to about 0.2% w/w, such as, e.g., from about 0.01%w/w to about 0.15% w/w, from about 0.02% w/w to about 0.12% w/w, fromabout 0.03% w/w to about 0.11% w/w, from about 0.04% w/w to about 0.1%w/w, from about 0.05% w/w to about 0.1% w/w, from about 0.06% w/w toabout 0.1% w/w or from about 0.07% w/w to about 0.09% w/w.

69. A snuff composition according to item 68, wherein the concentrationof the one or more sweeteners in the composition is about 0.08% w/w.

70. A snuff composition according to any of items 45-69, wherein thecomposition further comprises one or more flavouring agents such as mintflavour.

71. A snuff composition according to item 70, wherein the concentrationof the one or more flavouring agents in the composition is from about 1%w/w to about 15% w/w, such as, e.g., from about 1% w/w to about 10% w/w,from about 1.5% w/w to about 8% w/w, from about 2% w/w to about 6% w/wor from about 3% w/w to about 5% w/w.

72. A snuff composition according to item 71, wherein the concentrationof the one or more flavouring agents in the composition is about 4% w/w.

73. A snuff composition according to any of items 45-72, wherein thecomposition further comprises one or more buffering agents such as,e.g., a carbonate, a hydrogen carbonate or a phosphate including atriphosphate.

74. A snuff composition according to item 73, wherein the concentrationof the one or more buffering agents in the composition is from about0.1% w/w to about 5% w/w, such as, e.g., from about 0.2% w/w to about 4%w/w, from about 0.3% w/w to about 4% w/w, from about 0.4% w/w to about3% w/w, from about 0.5% w/w to about 2% w/w, from about 0.6% w/w toabout 1% w/w or from about 0.7% w/w to about 0.9% w/w.

75. A snuff composition according to item 74, wherein the concentrationof the one or more buffering agents in the composition is about 0.8%w/w.

76. A snuff composition according to any of items 45-75, wherein thecomposition further comprises one or more anti-oxidants in aconcentration of from about 0.4% w/w to about 2.4% w/w, such as, e.g.,from about 0.5% w/w to about 2.2% w/w, from about 0.6% w/w to about 2%w/w, from about 0.7% w/w to about 1.8% w/w or from about 0.8% w/w toabout 1.6% w/w.

The invention claimed is:
 1. A method for the preparation of anicotine-cellulose combination, the method comprising i) dissolving anicotine in an alcohol to form a nicotine solution, and ii) mixing thenicotine solution with a cellulose having a mean particle size of lessthan about 180 μm in a high-shear mixer for at the most 1 hour/kgcellulose employed under conditions suitable to simultaneously load thenicotine into voids or pores of the cellulose and agglomerate theparticles to obtain a nicotine-cellulose combination having a meanparticle size of from about 200 μm to about 500 μm and with a load ofnicotine of at least 5% v/v.
 2. A method according to claim 1, whereinthe temperature in the mixer is at the most about 30-40° C.
 3. A methodaccording to claim 1, wherein at the most 10% of the nicotine-cellulosecombination obtained has a particle size of 200 μm or less.
 4. A methodaccording to claim 1, further comprising drying the mixture resultingfrom step ii) by means of vacuum drying at the most at room temperature.5. A method according to claim 1, wherein the alcohol is ethanol in aconcentration of at least 98%.
 6. A method according to claim 5, whereinthe ethanol is in a concentration of at least 99%.
 7. A method accordingto claim 3, wherein at the most 5% of the nicotine-cellulose combinationobtained has a particle size of 200 μm or less.